Researcher: Fan Wang

Searching for self

by Jennifer Michalowski |

This story also appears in the Fall 2025 issue of BrainScan. 

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The question of how we know ourselves might seem the subject of philosophers, but it is just as much a matter of biology. As modern neuroscientists obtain an increasingly sophisticated understanding of how the brain generates emotions, responds to the external world, and learns from experience, some researchers are returning to a central question: How do we know our experiences, emotions, and physical sensations belong to us?

Curiosity about how the brain generates our sense of self has been a driving force for the research of McGovern Investigator Fan Wang. Following that curiosity has drawn Wang into diverse studies, exploring the origins of pain and the mechanisms we use to control our movements.

“We cannot pinpoint a set of active neurons and say that’s the sense of self. That still remains a mystery,” says Wang, who is also a professor of brain and cognitive sciences and co-director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT. But she and other neuroscientists are drilling down into different functions of the brain that together might generate our awareness of ourselves.

Woman wearing blue blazer smiles and gestures off camera with man in white lab coat seated next to her.
McGovern Investigator Fan Wang (right) with research scientist Vincent Prevosto, who studies brain regions implicated in whisker movement. Photo: Steph Stevens

Wang, who teaches the undergraduate course, “Neurobiology of Self,” explains that there are lots of ways to think about our sense of self, which are probably deeply integrated in the brain. Some are mostly about our physical bodies: How do we experience touch? How do we understand
where we are in space, or recognize the boundary between ourselves and rest of the world? Some consider more internal sensations, like how we experience pain or hunger. Emotion is also key to our sense of self: How do we know that anger or joy are our own, and why do these states change the way our bodies feel?

Wang can trace her initial interest in the brain’s sense of self to work she did as a graduate student in Richard Axel’s lab at Columbia University. The lab had identified receptors expressed by sensory neurons in the nose that detect odorous substances. Wang and others discovered the pathways that information about these smells takes to the brain, and how the brain distinguishes one smell from another.

Who is the “knower” of this information? “The answer,” Wang says, “is ‘I’ or ‘me.’ But understanding where I get the sense of self and how that is constructed, is what drives me to do neuroscience.”

Mechanisms of movement

In her lab at the McGovern Institute, Wang is studying how the brain controls the body’s movements, which she sees as closely tied to the awareness of our physical selves. “The reason I think I am in my body is because I can control my movement. I generate the movement. I cannot control your movement,” says Wang. “Volitional movement gives us a sense of agency, and this sense of agency resembles the sense of self.” For the mice that the group studies, one crucial type of movement comes from the whiskers, which the animals depend on as they explore their environments. Wang’s group has traced the neural circuity that controls whiskers’ rhythmic back-and-forth, which is initiated in the brainstem, where many of the body’s most vital functions are controlled. Wang describes the simple circuit as an oscillator, or a self-generated loop.

A maximum projection image showing tracked whiskers on the mouse muzzle. The right (control) side shows the back-and-forth rhythmic sweeping of the whiskers, while the experimental side where the whisking oscillator neurons are silenced, the whiskers move very little. Image: Wang Lab

Once it’s started, “the movement can go on unless some other signals stop it,” she says. The movement the circuit generates is simple but voluntary, and can be fine-tuned based on the sensory feedback the whiskers relay back to the brain. They’ve also been investigating how mice move the larynx to generate the squeaks and calls they use to communicate. These intentional movements must be coordinated with the ongoing cycles of respiration since we produce normal sounds only during expiration. Wang’s team has found neurons in the brainstem that generate vocalization-specific movements, and also discovered how respiration-controlling neural circuits can override them, ensuring that breathing is prioritized.

Wang says understanding the circuitry that controls these simple movements sets the stage for figuring out how the brain modifies activity in those circuits to create more complex, intentional movements. “That brings me closer to understanding where this volition is generated — and closer to this sense of self,” she says.

Emotional pain

Still, she knows that volitional movements — even those generated in response to perceptions of the environment — do not, on their own, define a sense of self. As a counterexample, she looks to self-driving cars: “There’s sensory information coming into the central computer, which then generates a motor output — where to drive, where to turn, where to stop. But none of us think a Waymo taxi has a sense of self.”

Wang says when she pondered the ways in which AI-powered cars lack a sense of self, she began thinking about emotions and pain. “If the self-driving Waymo crashes, it will not feel pain,” she says. “But if we hurt ourselves, we will feel pain. And we will hate that, and then we’ll learn.” So her lab is also exploring how the nervous system generates pain perception, including the emotional response that it evokes.

Ensembles of neurons in the amygdala activated by general anesthesia. Image: Fan Wang

In both humans and mice, pain causes emotional suffering that can be recognized and measured through changes in body functions like heart rate and blood pressure. With funding from the K. Lisa Yang Brain-Body Center at MIT, Wang’s lab is carefully tracking these involuntary, or autonomic, functions to gain a more complete understanding of pain’s emotional impact. This approach has helped clarify the role of pain-suppressing neurons in the brain’s amygdala — an important emotion-processing center — that Wang’s team discovered in 2020. When researchers selectively activate those cells in mice, the animals’ behavior makes it clear that the neurons are suppressing pain. Now, the group has learned that activating these neurons suppresses the autonomic response to pain.

Wang says there’s hope that modulating pain’s emotional response might be a way to treat chronic pain in patients. She explains that some patients with damage to another one of the brain’s emotional centers, the cingulate cortex, feel painful stimuli, but experience them as merely intense sensations. That suggests that it might be possible to modulate the emotional response to pain to eliminate patients’ suffering, without blocking the protective information that pain can provide.

The team has also been focusing on another set of anesthesia-activated neurons, which they have found suppress anxiety. When anxiety-suppressing neurons are activated in mice, the animals’ heart rates slow and they become more willing to explore bright, open spaces. Another anxiety-associated measure — heart rate variability — increases. Wang explains that this change is particularly significant: “If you have persistent low heart rate variability, especially in veterans, that is a very good predictor for anxiety developing into depression in the future,” she says.

The team’s findings, which suggest that changes in autonomic functions may themselves relieve anxiety, point toward potential new targets for anti-anxiety therapies. And by highlighting the connection between emotion and bodily responses, they offer more clues about our sense of self. “These neurons are now changing some high-level concept about anxiety,” Wang points out.

That link between emotion and body seems to Wang to be key to the sense of self. The big questions remain unanswered, but that simply stokes her curiosity. “I can be aware of my bodily responses: I am aware of ‘I am anxious’ or ‘I am in pain.’ I can see the pathways from which stimuli go into these nervous systems and come back down to the body and control the response. But I still don’t know who is the person — the knower,” she says. “I haven’t found it, so I’m going to keep looking.”

Seven with MIT ties elected to National Academy of Medicine for 2024

by Nina Tamburello | Koch Institute |

The National Academy of Medicine recently announced the election of more than 90 members during its annual meeting, including MIT faculty members Matthew Vander Heiden and Fan Wang, along with five MIT alumni.

Election to the National Academy of Medicine (NAM) is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

Matthew Vander Heiden is the director of the Koch Institute for Integrative Cancer Research at MIT, a Lester Wolfe Professor of Molecular Biology, and a member of the Broad Institute of MIT and Harvard. His research explores how cancer cells reprogram their metabolism to fuel tumor growth and has provided key insights into metabolic pathways that support cancer progression, with implications for developing new therapeutic strategies. The National Academy of Medicine recognized Vander Heiden for his contributions to “the development of approved therapies for cancer and anemia” and his role as a “thought leader in understanding metabolic phenotypes and their relations to disease pathogenesis.”

Vander Heiden earned his MD and PhD from the University of Chicago and completed  his clinical training in internal medicine and medical oncology at the Brigham and Women’s Hospital and the Dana-Farber Cancer Institute. After postdoctoral research at Harvard Medical School, Vander Heiden joined the faculty of the MIT Department of Biology and the Koch Institute in 2010. He is also a practicing oncologist and instructor in medicine at Dana-Farber Cancer Institute and Harvard Medical School.

Fan Wang is a professor of brain and cognitive sciences, an investigator at the McGovern Institute, and director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT.  Wang’s research focuses on the neural circuits governing the bidirectional interactions between the brain and body. She is specifically interested in the circuits that control the sensory and emotional aspects of pain and addiction, as well as the sensory and motor circuits that work together to execute behaviors such as eating, drinking, and moving. The National Academy of Medicine has recognized her body of work for “providing the foundational knowledge to develop new therapies to treat chronic pain and movement disorders.”

Before coming to MIT in 2021, Wang obtained her PhD from Columbia University and received her postdoctoral training at the University of California at San Francisco and Stanford University. She became a faculty member at Duke University in 2003 and was later appointed the Morris N. Broad Professor of Neurobiology. Wang is also a member of the American Academy of Arts and Sciences and she continues to make important contributions to the neural mechanisms underlying general anesthesia, pain perception, and movement control.

MIT alumni who were elected to the NAM for 2024 include:

  • Leemore Dafny PhD ’01 (Economics);
  • David Huang ’85 MS ’89  (Electrical Engineering and Computer Science) PhD ’93 Medical Engineering and Medical Physics);
  • Nola M. Hylton ’79 (Chemical Engineering);
  • Mark R. Prausnitz PhD ’94 (Chemical Engineering); and
  • Konstantina M. Stankovic ’92 (Biology and Physics) PhD ’98 (Speech and Hearing Bioscience and Technology)

Established originally as the Institute of Medicine in 1970 by the National Academy of Sciences, the National Academy of Medicine addresses critical issues in health, science, medicine, and related policy and inspires positive actions across sectors.

“This class of new members represents the most exceptional researchers and leaders in health and medicine, who have made significant breakthroughs, led the response to major public health challenges, and advanced health equity,” said National Academy of Medicine President Victor J. Dzau. “Their expertise will be necessary to supporting NAM’s work to address the pressing health and scientific challenges we face today.”

Harnessing the power of placebo for pain relief

by Jennifer Michalowski |

Placebos are inert treatments, generally not expected to impact biological pathways or improve a person’s physical health. But time and again, some patients report that they feel better after taking a placebo. Increasingly, doctors and scientists are recognizing that rather than dismissing placebos as mere trickery, they may be able to help patients by harnessing their power.

To maximize the impact of the placebo effect and design reliable therapeutic strategies, researchers need a better understanding of how it works. Now, with a new animal model developed by scientists at the McGovern Institute, they will be able to investigate the neural circuits that underlie placebos’ ability to elicit pain relief.

“The brain and body interaction has a lot of potential, in a way that we don’t fully understand,” says McGovern investigator Fan Wang. “I really think there needs to be more of a push to understand placebo effect, in pain and probably in many other conditions. Now we have a strong model to probe the circuit mechanism.”

Context-dependent placebo effect

McGovern Investigator Fan Wang. Photo: Caitliin Cunningham

In the September 5, 2024, issue of the journal Current Biology, Wang and her team report that they have elicited strong placebo pain relief in mice by activating pain-suppressing neurons in the brain while the mice are in a specific environment—thereby teaching the animals that they feel better when they are in that context. Following their training, placing the mice in that environment alone is enough to suppress pain. The team’s experiments, which were funded by the National Institutes of Health, the K. Lisa Yang Brain-Body Center and the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics within MIT’s Yang Tan Collective show that this context-dependent placebo effect relieves both acute and chronic pain.

Context is critical for the placebo effect. While a pill can help a patient feel better when they expect it to, even if it is made only of sugar or starch, it seems to be not just the pill that sets up those expectations, but the entire scenario in which the pill is taken. For example, being in a hospital and interacting with doctors can contribute to a patient’s perception of care, and these social and environmental factors can make a placebo effect more probable.

Postdoctoral fellows Bin Chen and Nitsan Goldstein used visual and textural cues to define a specific place. Then they activated pain-suppressing neurons in the brain while the animals were in this “pain-relief box.” Those pain-suppressing neurons, which Wang’s lab discovered a few years ago, are located in an emotion-processing center of the brain called the central amygdala. By expressing light-sensitive channels in these neurons, the researchers were able to suppress pain with light in the pain-relief box and leave the neurons inactive when mice were in a control box.

Animals learned to prefer the pain-relief box to other environments. And when the researchers tested their response to potentially painful stimuli after they had made that association, they found the mice were less sensitive while they were there. “Just by being in the context that they had associated with pain suppression, we saw that reduced pain—even though we weren’t actually activating those [pain-suppressing] neurons,” Goldstein explains.

Acute and chronic pain relief

Some scientists have been able to elicit placebo pain relief in rodents by treating the animals with morphine, linking environmental cues to the pain suppression caused by the drugs similar to the way Wang’s team did by directly activating pain-suppressing neurons. This drug-based approach works best for setting up expectations of relief for acute pain; its placebo effect is short-lived and mostly ineffective against chronic pain. So Wang, Chen, and Goldstein were particularly pleased to find that their engineered placebo effect was effective for relieving both acute and chronic pain.

In their experiments, animals experiencing a chemotherapy-induced hypersensitivity to touch exhibited a preference for the pain relief box as much as animals who were exposed to a chemical that induces acute pain, days after their initial conditioning. Once there, their chemotherapy-induced pain sensitivity was eliminated; they exhibited no more sensitivity to painful stimuli than they had prior to receiving chemotherapy.

One of the biggest surprises came when the researchers turned their attention back to the pain-suppressing neurons in the central amygdala that they had used to trigger pain relief. They suspected that those neurons might be reactivated when mice returned to the pain-relief box. Instead, they found that after the initial conditioning period, those neurons remained quiet. “These neurons are not reactivated, yet the mice appear to be no longer in pain,” Wang says. “So it suggests this memory of feeling well is transferred somewhere else.”

Goldstein adds that there must be a pain-suppressing neural circuit somewhere that is activated by pain-relief-associated contexts—and the team’s new placebo model sets researchers up to investigate those pathways. A deeper understanding of that circuitry could enable clinicians to deploy the placebo effect—alone or in combination with active treatments—to better manage patients’ pain in the future.

How the brain coordinates speaking and breathing

Anne Trafton |

MIT researchers have discovered a brain circuit that drives vocalization and ensures that you talk only when you breathe out, and stop talking when you breathe in.

McGovern Investigator Fan Wang. Photo: Caitliin Cunningham

The newly discovered circuit controls two actions that are required for vocalization: narrowing of the larynx and exhaling air from the lungs. The researchers also found that this vocalization circuit is under the command of a brainstem region that regulates the breathing rhythm, which ensures that breathing remains dominant over speech.

“When you need to breathe in, you have to stop vocalization. We found that the neurons that control vocalization receive direct inhibitory input from the breathing rhythm generator,” says Fan Wang, an MIT professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study.

Jaehong Park, a Duke University graduate student who is currently a visiting student at MIT, is the lead author of the study, which appears today in Science. Other authors of the paper include MIT technical associates Seonmi Choi and Andrew Harrahill, former MIT research scientist Jun Takatoh, and Duke University researchers Shengli Zhao and Bao-Xia Han.

Vocalization control

Located in the larynx, the vocal cords are two muscular bands that can open and close. When they are mostly closed, or adducted, air exhaled from the lungs generates sound as it passes through the cords.

The MIT team set out to study how the brain controls this vocalization process, using a mouse model. Mice communicate with each other using sounds known as ultrasonic vocalizations (USVs), which they produce using the unique whistling mechanism of exhaling air through a small hole between nearly closed vocal cords.

“We wanted to understand what are the neurons that control the vocal cord adduction, and then how do those neurons interact with the breathing circuit?” Wang says.

To figure that out, the researchers used a technique that allows them to map the synaptic connections between neurons. They knew that vocal cord adduction is controlled by laryngeal motor neurons, so they began by tracing backward to find the neurons that innervate those motor neurons.

This revealed that one major source of input is a group of premotor neurons found in the hindbrain region called the retroambiguus nucleus (RAm). Previous studies have shown that this area is involved in vocalization, but it wasn’t known exactly which part of the RAm was required or how it enabled sound production.

Image of green and magenta cells under a microscope.
Laryngeal premotor neurons (green) and Fos (magenta) labeling in the RAm. Image: Fan Wang

The researchers found that these synaptic tracing-labeled RAm neurons were strongly activated during USVs. This observation prompted the team to use an activity-dependent method to target these vocalization-specific RAm neurons, termed as RAmVOC. They used chemogenetics and optogenetics to explore what would happen if they silenced or stimulated their activity. When the researchers blocked the RAmVOC neurons, the mice were no longer able to produce USVs or any other kind of vocalization. Their vocal cords did not close, and their abdominal muscles did not contract, as they normally do during exhalation for vocalization.

Conversely, when the RAmVOC neurons were activated, the vocal cords closed, the mice exhaled, and USVs were produced. However, if the stimulation lasted two seconds or longer, these USVs would be interrupted by inhalations, suggesting that the process is under control of the same part of the brain that regulates breathing.

“Breathing is a survival need,” Wang says. “Even though these neurons are sufficient to elicit vocalization, they are under the control of breathing, which can override our optogenetic stimulation.”

Rhythm generation

Additional synaptic mapping revealed that neurons in a part of the brainstem called the pre-Bötzinger complex, which acts as a rhythm generator for inhalation, provide direct inhibitory input to the RAmVOC neurons.

“The pre-Bötzinger complex generates inhalation rhythms automatically and continuously, and the inhibitory neurons in that region project to these vocalization premotor neurons and essentially can shut them down,” Wang says.

This ensures that breathing remains dominant over speech production, and that we have to pause to breathe while speaking.

The researchers believe that although human speech production is more complex than mouse vocalization, the circuit they identified in mice plays the conserved role in speech production and breathing in humans.

“Even though the exact mechanism and complexity of vocalization in mice and humans is really different, the fundamental vocalization process, called phonation, which requires vocal cord closure and the exhalation of air, is shared in both the human and the mouse,” Park says.

The researchers now hope to study how other functions such as coughing and swallowing food may be affected by the brain circuits that control breathing and vocalization.

The research was funded by the National Institutes of Health.

Ariel Furst and Fan Wang receive 2023 National Institutes of Health awards

by MIT School of Science |

The National Institutes of Health (NIH) has awarded grants to MIT’s Ariel Furst and Fan Wang, through its High-Risk, High-Reward Research program. The NIH High-Risk, High-Reward Research program awarded 85 new research grants to support exceptionally creative scientists pursuing highly innovative behavioral and biomedical research projects.

Ariel Furst was selected as the recipient of the NIH Director’s New Innovator Award, which has supported unusually innovative research since 2007. Recipients are early-career investigators who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.

Furst, the Paul M. Cook Career Development Assistant Professor of Chemical Engineering at MIT, invents technologies to improve human and environmental health by increasing equitable access to resources. Her lab develops transformative technologies to solve problems related to health care and sustainability by harnessing the inherent capabilities of biological molecules and cells. She is passionate about STEM outreach and increasing the participation of underrepresented groups in engineering.

After completing her PhD at Caltech, where she developed noninvasive diagnostics for colorectal cancer, Furst became an A. O. Beckman Postdoctoral Fellow at the University of California at Berkeley. There she developed sensors to monitor environmental pollutants. In 2022, Furst was awarded the MIT UROP Outstanding Faculty Mentor Award for her work with undergraduate researchers. She is a now a 2023 Marion Milligan Mason Awardee, a CIFAR Azrieli Global Scholar for Bio-Inspired Solar Energy, and an ARO Early Career Grantee. She is also a co-founder of the regenerative agriculture company, Seia Bio.

Fan Wang received the Pioneer Award, which has been challenging researchers at all career levels to pursue new directions and develop groundbreaking, high impact approaches to a broad area of biomedical and behavioral sciences since 2004.

Wang, a professor in the Department of Brain and Cognitive Sciences and an investigator in the McGovern Institute for Brain Research, is uncovering the neural circuit mechanisms that govern bodily sensations, like touch, pain, and posture, as well as the mechanisms that control sensorimotor behaviors. Researchers in the Wang lab aim to generate an integrated understanding of the sensation-perception-action process, hoping to find better treatments for diseases like chronic pain, addiction, and movement disorders. Wang’s lab uses genetic, viral, in vivo large-scale electrophysiology and imaging techniques to gain traction in these pursuits.

Wang obtained her PhD at Columbia University, working with Professor Richard Axel. She conducted her postdoctoral work at Stanford University with Mark Tessier-Lavigne, and then subsequently joined Duke University as faculty in 2003. Wang was later appointed as the Morris N. Broad Distinguished Professor of Neurobiology at the Duke University School of Medicine. In January 2023, she joined the faculty of the MIT School of Science and the McGovern Institute.

The High-Risk, High-Reward Research program is funded through the NIH Common Fund, which supports a series of exceptionally high-impact programs that cross NIH Institutes and Centers.

“The HRHR program is a pillar for innovation here at NIH, providing support to transformational research, with advances in biomedical and behavioral science,” says Robert W. Eisinger, acting director of the Division of Program Coordination, Planning, and Strategic Initiatives, which oversees the NIH Common Fund. “These awards align with the Common Fund’s mandate to support science expected to have exceptionally high and broadly applicable impact.”

NIH issued eight Pioneer Awards, 58 New Innovator Awards, six Transformative Research Awards, and 13 Early Independence Awards in 2023. Funding for the awards comes from the NIH Common Fund; the National Institute of General Medical Sciences; the National Institute of Mental Health; the National Library of Medicine; the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Office of Dietary Supplements.

How touch dampens the brain’s response to painful stimuli

by Jennifer Michalowski |

McGovern Investigator Fan Wang. Photo: Caitliin Cunningham

When we press our temples to soothe an aching head or rub an elbow after an unexpected blow, it often brings some relief. It is believed that pain-responsive cells in the brain quiet down when these neurons also receive touch inputs, say scientists at MIT’s McGovern Institute, who for the first time have watched this phenomenon play out in the brains of mice.

The team’s discovery, reported November 16, 2022, in the journal Science Advances, offers researchers a deeper understanding of the complicated relationship between pain and touch and could offer some insights into chronic pain in humans. “We’re interested in this because it’s a common human experience,” says McGovern Investigator Fan Wang. “When some part of your body hurts, you rub it, right? We know touch can alleviate pain in this way.” But, she says, the phenomenon has been very difficult for neuroscientists to study.

Modeling pain relief

Touch-mediated pain relief may begin in the spinal cord, where prior studies have found pain-responsive neurons whose signals are dampened in response to touch. But there have been hints that the brain was involved too. Wang says this aspect of the response has been largely unexplored, because it can be hard to monitor the brain’s response to painful stimuli amidst all the other neural activity happening there—particularly when an animal moves.

So while her team knew that mice respond to a potentially painful stimulus on the cheek by wiping their faces with their paws, they couldn’t follow the specific pain response in the animals’ brains to see if that rubbing helped settle it down. “If you look at the brain when an animal is rubbing the face, movement and touch signals completely overwhelm any possible pain signal,” Wang explains.

She and her colleagues have found a way around this obstacle. Instead of studying the effects of face-rubbing, they have focused their attention on a subtler form of touch: the gentle vibrations produced by the movement of the animals’ whiskers. Mice use their whiskers to explore, moving them back and forth in a rhythmic motion known as whisking to feel out their environment. This motion activates touch receptors in the face and sends information to the brain in the form of vibrotactile signals. The human brain receives the same kind of touch signals when a person shakes their hand as they pull it back from a painfully hot pan—another way we seek touch-mediate pain relief.

If you look at the brain when an animal is rubbing the face, movement and touch signals completely overwhelm any possible pain signal, says Wang.

Wang and her colleagues found that this whisker movement alters the way mice respond to bothersome heat or a poke on the face—both of which usually lead to face rubbing. “When the unpleasant stimuli were applied in the presence of their self-generated vibrotactile whisking…they respond much less,” she says. Sometimes, she says, whisking animals entirely ignore these painful stimuli.

In the brain’s somatosensory cortex, where touch and pain signals are processed, the team found signaling changes that seem to underlie this effect. “The cells that preferentially respond to heat and poking are less frequently activated when the mice are whisking,” Wang says. “They’re less likely to show responses to painful stimuli.” Even when whisking animals did rub their faces in response to painful stimuli, the team found that neurons in the brain took more time to adopt the firing patterns associated with that rubbing movement. “When there is a pain stimulation, usually the trajectory the population dynamics quickly moved to wiping. But if you already have whisking, that takes much longer,” Wang says.

Wang notes that even in the fraction of a second before provoked mice begin rubbing their faces, when the animals are relatively still, it can be difficult to sort out which brain signals are related to perceiving heat and poking and which are involved in whisker movement. Her team developed computational tools to disentangle these, and are hoping other neuroscientists will use the new algorithms to make sense of their own data.

Whisking’s effects on pain signaling seem to depend on dedicated touch-processing circuitry that sends tactile information to the somatosensory cortex from a brain region called the ventral posterior thalamus. When the researchers blocked that pathway, whisking no longer dampened the animals’ response to painful stimuli. Now, Wang says, she and her team are eager to learn how this circuitry works with other parts of the brain to modulate the perception and response to painful stimuli.

Wang says the new findings might shed light on a condition called thalamic pain syndrome, a chronic pain disorder that can develop in patients after a stroke that affects the brain’s thalamus. “Such strokes may impair the functions of thalamic circuits that normally relay pure touch signals and dampen painful signals to the cortex,” she says.

Personal pursuits

by Jennifer Michalowski |

This story originally appeared in the Fall 2022 issue of BrainScan.

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Many neuroscientists were drawn to their careers out of curiosity and wonder. Their deep desire to understand how the brain works drew them into the lab and keeps them coming back, digging deeper and exploring more each day. But for some, the work is more personal.

Several McGovern faculty say they entered their field because someone in their lives was dealing with a brain disorder that they wanted to better understand. They are committed to unraveling the basic biology of those conditions, knowing that knowledge is essential to guide the development of better treatments.

The distance from basic research to clinical progress is shortening, and many young neuroscientists hope not just to deepen scientific understanding of the brain, but to have direct impact on the lives of patients. Some want to know why people they love are suffering from neurological disorders or mental illness; others seek to understand the ways in which their own brains work differently than others. But above all, they want better treatments for people affected by such disorders.

Seeking answers

That’s true for Kian Caplan, a graduate student in MIT’s Department of Brain and Cognitive Sciences who was diagnosed with Tourette syndrome around age 13. At the time, learning that the repetitive, uncontrollable movements and vocal tics he had been making for most of his life were caused by a neurological disorder was something of a relief. But it didn’t take long for Caplan to realize his diagnosis came with few answers.

Graduate student Kian Caplan studies the brain circuits associated with Tourette syndrome and obsessive-compulsive disorder in Guoping Feng and Fan Wang’s labs at the McGovern Institute. Photo: Steph Stevens

Tourette syndrome has been estimated to occur in about six of every 1,000 children, but its neurobiology remains poorly understood.

“The doctors couldn’t really explain why I can’t control the movements and sounds I make,” he says. “They couldn’t really explain why my symptoms wax and wane, or why the tics I have aren’t always the same.”

That lack of understanding is not just frustrating for curious kids like Caplan. It means that researchers have been unable to develop treatments that target the root cause of Tourette syndrome. Drugs that dampen signaling in parts of the brain that control movement can help suppress tics, but not without significant side effects. Caplan has tried those drugs. For him, he says, “they’re not worth the suppression.”

Advised by Fan Wang and McGovern Associate Director Guoping Feng, Caplan is looking for answers. A mouse model of obsessive-compulsive disorder developed in Feng’s lab was recently found to exhibit repetitive movements similar to those of people with Tourette syndrome, and Caplan is working to characterize those tic-like movements. He will use the mouse model to examine the brain circuits underlying the two conditions, which often co-occur in people. Broadly, researchers think Tourette syndrome arises due to dysregulation of cortico-striatal-thalamo-cortical circuits, which connect distant parts of the brain to control movement. Caplan and Wang suspect that the brainstem — a structure found where the brain connects to the spinal cord, known for organizing motor movement into different modules — is probably involved, too.

Wang’s research group studies the brainstem’s role in movement, but she says that like most researchers, she hadn’t considered its role in Tourette syndrome until Caplan joined her lab. That’s one reason Caplan, who has long been a mentor and advocate for students with neurodevelopmental disorders, thinks neuroscience needs more neurodiversity.

“I think we need more representation in basic science research by the people who actually live with those conditions,” he says. Their experiences can lead to insights that may be inaccessible to others, he says, but significant barriers in academia often prevent this kind of representation. Caplan wants to see institutions make systemic changes to ensure that neurodiverse and otherwise minority individuals are able to thrive in academia. “I’m not an exception,” he says, “there should be more people like me here, but the present system makes that incredibly difficult.”

Overcoming adversity

Like Caplan, Lace Riggs faced significant challenges in her pursuit to study the brain. She grew up in Southern California’s Inland Empire, where issues of social disparity, chronic stress, drug addiction, and mental illness were a part of everyday life.

Postdoctoral fellow Lace Riggs studies the origins of neurodevelopmental conditions in Guoping Feng’s lab at the McGovern Institute. Photo: Lace Riggs

“Living in severe poverty and relying on government assistance without access to adequate education and resources led everyone I know and love to suffer tremendously, myself included,” says Riggs, a postdoctoral fellow in the Feng lab.

“There are not a lot of people like me who make it to this stage,” says Riggs, who has lost friends and family members to addiction, mental illness, and suicide. “There’s a reason for that,” she adds. “It’s really, really difficult to get through the educational system and to overcome socioeconomic barriers.”

Today, Riggs is investigating the origins of neurodevelopmental conditions, hoping to pave the way to better treatments for brain disorders by uncovering the molecular changes that alter the structure and function of neural circuits.

Riggs says that the adversities she faced early in life offered valuable insights in the pursuit of these goals. She first became interested in the brain because she wanted to understand how our experiences have a lasting impact on who we are — including in ways that leave people vulnerable to psychiatric problems.

“While the need for more effective treatments led me to become interested in psychiatry, my fascination with the brain’s unique ability to adapt is what led me to neuroscience,” says Riggs.

After finishing high school, Riggs attended California State University in San Bernardino and became the only member of her family to attend university or attempt a four-year degree. Today, she spends her days working with mice that carry mutations linked to autism or ADHD in humans, studying the animals’ behavior and monitoring their neural activity. She expects that aberrant neural circuit activity in these conditions may also contribute to mood disorders, whose origins are harder to tease apart because they often arise when genetic and environmental factors intersect. Ultimately, Riggs says, she wants to understand how our genes dictate whether an experience will alter neural signaling and impact mental health in a long-lasting way.

Riggs uses patch clamp electrophysiology to record the strength of inhibitory and excitatory synaptic input onto individual neurons (white arrow) in an animal model of autism. Image: Lace Riggs

“If we understand how these long-lasting synaptic changes come about, then we might be able to leverage these mechanisms to develop new and more effective treatments.”

While the turmoil of her childhood is in the past, Riggs says it is not forgotten — in part, because of its lasting effects on her own mental health.  She talks openly about her ongoing struggle with social anxiety and complex post-traumatic stress disorder because she is passionate about dismantling the stigma surrounding these conditions. “It’s something I have to deal with every day,” Riggs says. That means coping with symptoms like difficulty concentrating, hypervigilance, and heightened sensitivity to stress. “It’s like a constant hum in the background of my life, it never stops,” she says.

“I urge all of us to strive, not only to make scientific discoveries to move the field forward,” says Riggs, “but to improve the accessibility of this career to those whose lived experiences are required to truly accomplish that goal.”

How the brain generates rhythmic behavior

Anne Trafton |

Many of our bodily functions, such as walking, breathing, and chewing, are controlled by brain circuits called central oscillators, which generate rhythmic firing patterns that regulate these behaviors.

MIT neuroscientists have now discovered the neuronal identity and mechanism underlying one of these circuits: an oscillator that controls the rhythmic back-and-forth sweeping of tactile whiskers, or whisking, in mice. This is the first time that any such oscillator has been fully characterized in mammals.

The MIT team found that the whisking oscillator consists of a population of inhibitory neurons in the brainstem that fires rhythmic bursts during whisking. As each neuron fires, it also inhibits some of the other neurons in the network, allowing the overall population to generate a synchronous rhythm that retracts the whiskers from their protracted positions.

“We have defined a mammalian oscillator molecularly, electrophysiologically, functionally, and mechanistically,” says Fan Wang, an MIT professor of brain and cognitive sciences and a member of MIT’s McGovern Institute for Brain Research. “It’s very exciting to see a clearly defined circuit and mechanism of how rhythm is generated in a mammal.”

Wang is the senior author of the study, which appears today in Nature. The lead authors of the paper are MIT research scientists Jun Takatoh and Vincent Prevosto.

Rhythmic behavior

Most of the research that clearly identified central oscillator circuits has been done in invertebrates. For example, Eve Marder’s lab at Brandeis University found cells in the stomatogastric ganglion in lobsters and crabs that generate oscillatory activity to control rhythmic motion of the digestive tract.

Characterizing oscillators in mammals, especially in awake behaving animals, has proven to be highly challenging. The oscillator that controls walking is believed to be distributed throughout the spinal cord, making it difficult to precisely identify the neurons and circuits involved. The oscillator that generates rhythmic breathing is located in a part of the brain stem called the pre-Bötzinger complex, but the exact identity of the oscillator neurons is not fully understood.

“There haven’t been detailed studies in awake behaving animals, where one can record from molecularly identified oscillator cells and manipulate them in a precise way,” Wang says.

Whisking is a prominent rhythmic exploratory behavior in many mammals, which use their tactile whiskers to detect objects and sense textures. In mice, whiskers extend and retract at a frequency of about 12 cycles per second. Several years ago, Wang’s lab set out try to identify the cells and the mechanism that control this oscillation.

To find the location of the whisking oscillator, the researchers traced back from the motor neurons that innervate whisker muscles. Using a modified rabies virus that infects axons, the researchers were able to label a group of cells presynaptic to these motor neurons in a part of the brainstem called the vibrissa intermediate reticular nucleus (vIRt). This finding was consistent with previous studies showing that damage to this part of the brain eliminates whisking.

The researchers then found that about half of these vIRt neurons express a protein called parvalbumin, and that this subpopulation of cells drives the rhythmic motion of the whiskers. When these neurons are silenced, whisking activity is abolished.

Next, the researchers recorded electrical activity from these parvalbumin-expressing vIRt neurons in brainstem in awake mice, a technically challenging task, and found that these neurons indeed have bursts of activity only during the whisker retraction period. Because these neurons provide inhibitory synaptic inputs to whisker motor neurons, it follows that rhythmic whisking is generated by a constant motor neuron protraction signal interrupted by the rhythmic retraction signal from these oscillator cells.

“That was a super satisfying and rewarding moment, to see that these cells are indeed the oscillator cells, because they fire rhythmically, they fire in the retraction phase, and they’re inhibitory neurons,” Wang says.

A maximum projection image showing tracked whiskers on the mouse muzzle. The right (control) side shows the back-and-forth rhythmic sweeping of the whiskers, while the experimental side where the whisking oscillator neurons are silenced, the whiskers move very little. Image: Wang Lab

“New principles”

The oscillatory bursting pattern of vIRt cells is initiated at the start of whisking. When the whiskers are not moving, these neurons fire continuously. When the researchers blocked vIRt neurons from inhibiting each other, the rhythm disappeared, and instead the oscillator neurons simply increased their rate of continuous firing.

This type of network, known as recurrent inhibitory network, differs from the types of oscillators that have been seen in the stomatogastric neurons in lobsters, in which neurons intrinsically generate their own rhythm.

“Now we have found a mammalian network oscillator that is formed by all inhibitory neurons,” Wang says.

The MIT scientists also collaborated with a team of theorists led by David Golomb at Ben-Gurion University, Israel, and David Kleinfeld at the University of California at San Diego. The theorists created a detailed computational model outlining how whisking is controlled, which fits well with all experimental data. A paper describing that model is appearing in an upcoming issue of Neuron.

Wang’s lab now plans to investigate other types of oscillatory circuits in mice, including those that control chewing and licking.

“We are very excited to find oscillators of these feeding behaviors and compare and contrast to the whisking oscillator, because they are all in the brain stem, and we want to know whether there’s some common theme or if there are many different ways to generate oscillators,” she says.

The research was funded by the National Institutes of Health.

New research center focused on brain-body relationship established at MIT

by Julie Pryor |

The inextricable link between our brains and our bodies has been gaining increasing recognition among researchers and clinicians over recent years. Studies have shown that the brain-body pathway is bidirectional — meaning that our mental state can influence our physical health and vice versa. But exactly how the two interact is less clear.

A new research center at MIT, funded by a $38 million gift to the McGovern Institute for Brain Research from philanthropist K. Lisa Yang, aims to unlock this mystery by creating and applying novel tools to explore the multidirectional, multilevel interplay between the brain and other body organ systems. This gift expands Yang’s exceptional philanthropic support of human health and basic science research at MIT over the past five years.

“Lisa Yang’s visionary gift enables MIT scientists and engineers to pioneer revolutionary technologies and undertake rigorous investigations into the brain’s complex relationship with other organ systems,” says MIT President L. Rafael Reif.  “Lisa’s tremendous generosity empowers MIT scientists to make pivotal breakthroughs in brain and biomedical research and, collectively, improve human health on a grand scale.”

The K. Lisa Yang Brain-Body Center will be directed by Polina Anikeeva, professor of materials science and engineering and brain and cognitive sciences at MIT and an associate investigator at the McGovern Institute. The center will harness the power of MIT’s collaborative, interdisciplinary life sciences research and engineering community to focus on complex conditions and diseases affecting both the body and brain, with a goal of unearthing knowledge of biological mechanisms that will lead to promising therapeutic options.

“Under Professor Anikeeva’s brilliant leadership, this wellspring of resources will encourage the very best work of MIT faculty, graduate fellows, and research — and ultimately make a real impact on the lives of many,” Reif adds.

microscope image of gut
Mouse small intestine stained to reveal cell nucleii (blue) and peripheral nerve fibers (red).
Image: Polina Anikeeva, Marie Manthey, Kareena Villalobos

Center goals  

Initial projects in the center will focus on four major lines of research:

  • Gut-Brain: Anikeeva’s group will expand a toolbox of new technologies and apply these tools to examine major neurobiological questions about gut-brain pathways and connections in the context of autism spectrum disorders, Parkinson’s disease, and affective disorders.
  • Aging: CRISPR pioneer Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and investigator at the McGovern Institute, will lead a group in developing molecular tools for precision epigenomic editing and erasing accumulated “errors” of time, injury, or disease in various types of cells and tissues.
  • Pain: The lab of Fan Wang, investigator at the McGovern Institute and professor of brain and cognitive sciences, will design new tools and imaging methods to study autonomic responses, sympathetic-parasympathetic system balance, and brain-autonomic nervous system interactions, including how pain influences these interactions.
  • Acupuncture: Wang will also collaborate with Hilda (“Scooter”) Holcombe, a veterinarian in MIT’s Division of Comparative Medicine, to advance techniques for documenting changes in brain and peripheral tissues induced by acupuncture in mouse models. If successful, these techniques could lay the groundwork for deeper understandings of the mechanisms of acupuncture, specifically how the treatment stimulates the nervous system and restores function.

A key component of the K. Lisa Yang Brain-Body Center will be a focus on educating and training the brightest young minds who aspire to make true breakthroughs for individuals living with complex and often devastating diseases. A portion of center funding will endow the new K. Lisa Yang Brain-Body Fellows Program, which will support four annual fellowships for MIT graduate students and postdocs working to advance understanding of conditions that affect both the body and brain.

Mens sana in corpore sano

“A phrase I remember reading in secondary school has always stuck with me: ‘mens sana in corpore sano’ — ‘a healthy mind in a healthy body,’” says Lisa Yang, a former investment banker committed to advocacy for individuals with visible and invisible disabilities. “When we look at how stress, nutrition, pain, immunity, and other complex factors impact our health, we truly see how inextricably linked our brains and bodies are. I am eager to help MIT scientists and engineers decode these links and make real headway in creating therapeutic strategies that result in longer, healthier lives.”

“This center marks a once-in-a-lifetime opportunity for labs like mine to conduct bold and risky studies into the complexities of brain-body connections,” says Anikeeva, who works at the intersection of materials science, electronics, and neurobiology. “The K. Lisa Yang Brain-Body Center will offer a pathbreaking, holistic approach that bridges multiple fields of study. I have no doubt that the center will result in revolutionary strides in our understanding of the inextricable bonds between the brain and the body’s peripheral organ systems, and a bold new way of thinking in how we approach human health overall.”

On a mission to alleviate chronic pain

Anne Trafton |

About 50 million Americans suffer from chronic pain, which interferes with their daily life, social interactions, and ability to work. MIT Professor Fan Wang wants to develop new ways to help relieve that pain, by studying and potentially modifying the brain’s own pain control mechanisms.

Her recent work has identified an “off switch” for pain, located in the brain’s amygdala. She hopes that finding ways to control this switch could lead to new treatments for chronic pain.

“Chronic pain is a major societal issue,” Wang says. “By studying pain-suppression neurons in the brain’s central amygdala, I hope to create a new therapeutic approach for alleviating pain.”

Wang, who joined the MIT faculty in January 2021, is also the leader of a new initiative at the McGovern Institute for Brain Research that is studying drug addiction, with the goal of developing more effective treatments for addiction.

“Opioid prescription for chronic pain is a major contributor to the opioid epidemic. With the Covid pandemic, I think addiction and overdose are becoming worse. People are more anxious, and they seek drugs to alleviate such mental pain,” Wang says. “As scientists, it’s our duty to tackle this problem.”

Sensory circuits

Wang, who grew up in Beijing, describes herself as “a nerdy child” who loved books and math. In high school, she took part in science competitions, then went on to study biology at Tsinghua University. She arrived in the United States in 1993 to begin her PhD at Columbia University. There, she worked on tracing the connection patterns of olfactory receptor neurons in the lab of Richard Axel, who later won the Nobel Prize for his discoveries of odorant receptors and how the olfactory system is organized.

After finishing her PhD, Wang decided to switch gears. As a postdoc at the University of California at San Francisco and then Stanford University, she began studying how the brain perceives touch.

In 2003, Wang joined the faculty at Duke University School of Medicine. There, she began developing techniques to study the brain circuits that underlie the sense of touch, tracing circuits that carry sensory information from the whiskers of mice to the brain. She also studied how the brain integrates movements of touch organs with signals of sensory stimuli to generate perception (such as using stretching movements to sense elasticity).

As she pursued her sensory perception studies, Wang became interested in studying pain perception, but she felt she needed to develop new techniques to tackle it. While at Duke, she invented a technique called CANE (capturing activated neural ensembles), which can identify networks of neurons that are activated by a particular stimulus.

Using this approach in mice, she identified neurons that become active in response to pain, but so many neurons across the brain were activated that it didn’t offer much useful information. As a way to indirectly get at how the brain controls pain, she decided to use CANE to explore the effects of drugs used for general anesthesia. During general anesthesia, drugs render a patient unconscious, but Wang hypothesized that the drugs might also shut off pain perception.

“At that time, it was just a wild idea,” Wang recalls. “I thought there may be other mechanisms — that instead of just a loss of consciousness, anesthetics may do something to the brain that actually turns pain off.”

Support for the existence of an “off switch” for pain came from the observation that wounded soldiers on a battlefield can continue to fight, essentially blocking out pain despite their injuries.

In a study of mice treated with anesthesia drugs, Wang discovered that the brain does have this kind of switch, in an unexpected location: the amygdala, which is involved in regulating emotion. She showed that this cluster of neurons can turn off pain when activated, and when it is suppressed, mice become highly sensitive to ordinary gentle touch.

“There’s a baseline level of activity that makes the animals feel normal, and when you activate these neurons, they’ll feel less pain. When you silence them, they’ll feel more pain,” Wang says.

Turning off pain

That finding, which Wang reported in 2020, raised the possibility of somehow modulating that switch in humans to try to treat chronic pain. This is a long-term goal of Wang’s, but more work is required to achieve it, she says. Currently her lab is working on analyzing the RNA expression patterns of the neurons in the cluster she identified. They also are measuring the neurons’ electrical activity and how they interact with other neurons in the brain, in hopes of identifying circuits that could be targeted to tamp down the perception of pain.

One way of modulating these circuits could be to use deep brain stimulation, which involves implanting electrodes in certain areas of the brain. Focused ultrasound, which is still in early stages of development and does not require surgery, could be a less invasive alternative.

Another approach Wang is interested in exploring is pairing brain stimulation with a context such as looking at a smartphone app. This kind of pairing could help train the brain to shut off pain using the app, without the need for the original stimulation (deep brain stimulation or ultrasound).

“Maybe you don’t need to constantly stimulate the brain. You may just need to reactivate it with a context,” Wang says. “After a while you would probably need to be restimulated, or reconditioned, but at least you have a longer window where you don’t need to go to the hospital for stimulation, and you just need to use a context.”

Wang, who was drawn to MIT in part by its focus on fostering interdisciplinary collaborations, is now working with several other McGovern Institute members who are taking different angles to try to figure out how the brain generates the state of craving that occurs in drug addiction, including opioid addiction.

“We’re going to focus on trying to understand this craving state: how it’s created in the brain and how can we sort of erase that trace in the brain, or at least control it. And then you can neuromodulate it in real time, for example, and give people a chance to get back their control,” she says.